Despite the long history of studying the effects of radiation on normal tissues in vitro and in vivo, there is a dearth of agents immediately available for mitigating radiation injury. The UCLA-CMCR has developed an infrastructure that allows discovery and evaluation of such agents. Most of this effort went into an unbiased approach to drug discovery that employs high throughput screening (HTS) of libraries of chemically defined or known bioactive small molecules using yeast, murine, and human systems and multiple endpoints. Importantly, Projects 1 and 2, which will continue, identified lead compounds and classes of compounds from both types of libraries that can mitigate damage in vivo when given to mice 24 hrs after lethal whole body radiation doses. Core chemical structures have been identified, so part of the focus in the next funding period will be on synthesizing analogues to hone in on the critical elements responsible for activity, with a view to optimizing drug effectiveness and delivery through pharmaceutical chemistry. We have validated our original concept that molecular and chemical signatures can be used to classify modulators of radiation responses and that these can then be exploited for rational development of effective mitigating agents. We have knowledge of mechanisms for several classes of compounds, but several others still need to be further investigated. Some act through Toll-like receptors, as described in this application, and Project 3 now focuses on this pathway. Further drug discovery efforts are underway. The UCLA-CMCR has harnessed multiple strengths at UCLA with benefit to the CMCR program and has built a rich environment for research, training, and product development in the radiation sciences. This renewal incorporates investigators, information, and experimental systems from eight pilot projects, in addition to existing personnel. All information is stored on an industrial-strength database so that all CMCRs can have access for analysis and data mining. We interact with other members of the CMCR network and with groups and individuals in academic and commercial entities to test and compare mitigators. In brief, the UCLA-CMCR has made great progress and has developed many promising avenues for future exploration.